PROJECT SUMMARY The type 2 immune response is triggered by intestinal helminth infection and is characterized by elevations in IL-4, IL-5, IL-13 and other Th2 cytokines. The factors that initiate the type 2 immune response are not yet well understood and may include release of danger associated molecular patterns, which may be triggered by tissue damage resulting from intestinal helminths migrating through body tissues. We have recently identified adenosine, specifically interacting with the A2B adenosine receptor (AR) as a potential danger associated molecular pattern that may be essential for the development of type 2 immune response to the intestinal nematode parasite, H. polygyrus. Our studies showed that the intestinal immune response to H. polygyrus is markedly impaired in A2BAR-/- mice and in wild-type mice given A2BAR antagonists. Our findings further indicate that mRNA upregulation of the cytokine alarmin, IL-33, is inhibited by A2BAR blockade, raising the possibility that one mechanism through which A2BAR signaling initiates type 2 immunity is through influencing IL-33 production. In our proposed studies we will examine the role of A2BAR signaling in triggering the release and subsequent upregulation of IL-33 gene and protein expression. We will further examine specific targets of A2BAR signaling, including epithelial cells and macrophages, and specifically examine how A2BAR affects the development of the type 2 primary and memory immune response to H. polygyrus. The mechanisms of adenosine accumulation, including release and degradation of its precursor ATP will also be studied. These studies will elucidate the role of adenosine as an endogenous danger signal in the initiation and the development of the mucosal type 2 immune response and as such will provide significant insights as to how this important type of immune response may develop.